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Memory-like Differentiation Enhances NK Cell Responses to Melanoma
Clinical Cancer Research ( IF 11.5 ) Pub Date : 2021-09-01 , DOI: 10.1158/1078-0432.ccr-21-0851
Nancy D Marin 1 , Bradley A Krasnick 2 , Michelle Becker-Hapak 1 , Leah Conant 2 , Simon P Goedegebuure 2 , Melissa M Berrien-Elliott 1 , Keenan J Robbins 2 , Jennifer A Foltz 1 , Mark Foster 1 , Pamela Wong 1 , Celia C Cubitt 1 , Jennifer Tran 1 , Christopher B Wetzel 2 , Miriam Jacobs 1 , Alice Y Zhou 1 , David Russler-Germain 1 , Lynne Marsala 1 , Timothy Schappe 1 , Ryan C Fields 2 , Todd A Fehniger 1
Affiliation  

Purpose: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell–refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined. Experimental Design: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNγ and kill melanoma targets in vitro and in vivo using a xenograft model. Results: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNγ production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D- and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells. Conclusions: Blood NK cells from allogeneic HD or patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials.

中文翻译:

记忆样分化增强 NK 细胞对黑色素瘤的反应

目的:晚期黑色素瘤的治疗是一项临床挑战。自然杀伤 (NK) 细胞是治疗 T 细胞难治性癌症的一种很有前途的细胞疗法,但在黑色素瘤患者中经常出现缺陷或功能失调。因此,需要新的策略来增强 NK 细胞的抗肿瘤反应。细胞因子诱导的记忆样 (ML) 分化克服了 NK 细胞治疗领域的许多障碍,从而产生强大的细胞毒性并增强了针对血癌靶标的细胞因子产生。然而,ML NK 对实体瘤的临床前活性在很大程度上仍未明确。实验设计:使用质谱流式细胞术评估血液和晚期黑色素瘤浸润 NK 细胞的表型和功能改变。使用异种移植模型评估来自健康供体 (HD) 和晚期黑色素瘤患者的 ML NK 细胞在体外和体内产生 IFNγ 和杀死黑色素瘤靶标的能力。结果:与血液 NK 细胞相比,晚期黑色素瘤中的 NK 细胞表现出细胞毒性降低。从 HD 和晚期黑色素瘤患者分化而来的 ML NK 细胞显示出增强的 IFNγ 产生和针对黑色素瘤靶标的细胞毒性。这包括 ML 分化增强黑色素瘤患者的 NK 细胞对自体靶标的反应。ML NK 细胞对黑色素瘤的反应部分依赖于 NKG2D 和 NKp46 激活受体。此外,在异种移植 NSG 小鼠模型中,与传统 NK 细胞相比,人类 ML NK 细胞表现出对黑色素瘤的卓越控制。结论:
更新日期:2021-09-01
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